Angiotensin-Converting Enzyme 2: The First Decade

The renin-angiotensin system (RAS) is a critical regulator of hypertension, primarily through the actions of the vasoactive peptide Ang II, which is generated by the action of angiotensin-converting enzyme (ACE) mediating an increase in blood pressure. The discovery of ACE2, which primarily metabolises Ang II into the vasodilatory Ang-(1-7), has added a new dimension to the traditional RAS. As a result there has been huge interest in ACE2 over the past decade as a potential therapeutic for lowering blood pressure, especially elevation resulting from excess Ang II. Studies focusing on ACE2 have helped to reveal other actions of Ang-(1-7), outside vasodilation, such as antifibrotic and antiproliferative effects. Moreover, investigations focusing on ACE2 have revealed a variety of roles not just catalytic but also as a viral receptor and amino acid transporter. This paper focuses on what is known about ACE2 and its biological roles, paying particular attention to the regulation of ACE2 expression. In light of the entrance of human recombinant ACE2 into clinical trials, we discuss the potential use of ACE2 as a therapeutic and highlight some pertinent questions that still remain unanswered about ACE2

Towards a Formal Verification Methodology for Collective Robotic Systems

We introduce a UML-based notation for graphically modeling systems’ security aspects in a simple and intuitive way and a model-driven process that transforms graphical specifications of access control policies in XACML. These XACML policies are then translated in FACPL, a policy language with a formal semantics, and the resulting policies are evaluated by means of a Java-based software tool

A Logical Verification Methodology for Service-Oriented Computing

We introduce a logical verification methodology for checking behavioural properties of service-oriented computing systems. Service properties are described by means of SocL, a branching-time temporal logic that we have specifically designed to express in an effective way distinctive aspects of services, such as, e.g., acceptance of a request, provision of a response, and correlation among service requests and responses. Our approach allows service properties to be expressed in such a way that they can be independent of service domains and specifications. We show an instantiation of our general methodology that uses the formal language COWS to conveniently specify services and the expressly developed software tool CMC to assist the user in the task of verifying SocL formulae over service specifications. We demonstrate feasibility and effectiveness of our methodology by means of the specification and the analysis of a case study in the automotive domain

Evidence for a lineage of virulent bacteriophages that target Campylobacter.

BACKGROUND: Our understanding of the dynamics of genome stability versus gene flux within bacteriophage lineages is limited. Recently, there has been a renewed interest in the use of bacteriophages as 'therapeutic' agents; a prerequisite for their use in such therapies is a thorough understanding of their genetic complement, genome stability and their ecology to avoid the dissemination or mobilisation of phage or bacterial virulence and toxin genes. Campylobacter, a food-borne pathogen, is one of the organisms for which the use of bacteriophage is being considered to reduce human exposure to this organism. RESULTS: Sequencing and genome analysis was performed for two Campylobacter bacteriophages. The genomes were extremely similar at the nucleotide level (> or = 96%) with most differences accounted for by novel insertion sequences, DNA methylases and an approximately 10 kb contiguous region of metabolic genes that were dissimilar at the sequence level but similar in gene function between the two phages. Both bacteriophages contained a large number of radical S-adenosylmethionine (SAM) genes, presumably involved in boosting host metabolism during infection, as well as evidence that many genes had been acquired from a wide range of bacterial species. Further bacteriophages, from the UK Campylobacter typing set, were screened for the presence of bacteriophage structural genes, DNA methylases, mobile genetic elements and regulatory genes identified from the genome sequences. The results indicate that many of these bacteriophages are related, with 10 out of 15 showing some relationship to the sequenced genomes. CONCLUSIONS: Two large virulent Campylobacter bacteriophages were found to show very high levels of sequence conservation despite separation in time and place of isolation. The bacteriophages show adaptations to their host and possess genes that may enhance Campylobacter metabolism, potentially advantaging both the bacteriophage and its host. Genetic conservation has been shown to extend to other Campylobacter bacteriophages, forming a highly conserved lineage of bacteriophages that predate upon campylobacters and indicating that highly adapted bacteriophage genomes can be stable over prolonged periods of time

Airborne sampling of aerosol particles: Comparison between surface sampling at Christmas Island and P-3 sampling during PEM-Tropics B

Bulk aerosol sampling of soluble ionic compounds from the NASA Wallops Island P-3 aircraft and a tower on Christmas Island during PEM-Tropics B provides an opportunity to assess the magnitude of particle losses in the University of New Hampshire airborne bulk aerosol sampling system. We find that most aerosol-associated ions decrease strongly with height above the sea surface, making direct comparisons between mixing ratios at 30 m on the tower and the lowest flight level of the P-3 (150 m) open to interpretation. Theoretical considerations suggest that vertical gradients of sea-salt aerosol particles should show exponential decreases with height. Observed gradients of Na+ and Mg2+, combining the tower observations with P-3 samples collected below 1 km, are well described by exponential decreases (r values of 0.88 and 0.87, respectively), though the curve fit underestimates average mixing ratios at the surface by 25%. Cascade impactor samples collected on the tower show that \u3e99% of the Na+ and Mg2+mass is on supermicron particles, 65% is in the 1–6 micron range, and just 20% resides on particles with diameters larger than 9 microns. These results indicate that our airborne aerosol sampling probes must be passing particles up to at least 6 microns with high efficiency. We also observed that nss SO42− and NH4+, which are dominantly on accumulation mode particles, tended to decrease between 150 and 1000 m, but they were often considerably higher at the lowest P-3 sampling altitudes than at the tower. This finding is presently not well understood

Checkpoint inhibition of origin firing prevents DNA topological stress.

A universal feature of DNA damage and replication stress in eukaryotes is the activation of a checkpoint-kinase response. In S-phase, the checkpoint inhibits replication initiation, yet the function of this global block to origin firing remains unknown. To establish the physiological roles of this arm of the checkpoint, we analyzed separation of function mutants in the budding yeast Saccharomyces cerevisiae that allow global origin firing upon replication stress, despite an otherwise normal checkpoint response. Using genetic screens, we show that lack of the checkpoint-block to origin firing results in a dependence on pathways required for the resolution of topological problems. Failure to inhibit replication initiation indeed causes increased DNA catenation, resulting in DNA damage and chromosome loss. We further show that such topological stress is not only a consequence of a failed checkpoint response but also occurs in an unperturbed S-phase when too many origins fire simultaneously. Together we reveal that the role of limiting the number of replication initiation events is to prevent DNA topological problems, which may be relevant for the treatment of cancer with both topoisomerase and checkpoint inhibitors

Inheritance of Temporal Logic Properties

Abstract. Inheritance is one of the key features for the success of object-oriented languages. Inheritance (or specialisation) supports incremental design and re-use of already written specifications or programs. In a for-mal approach to system design the interest does not only lie in re-use of class definitions but also in re-use of correctness proofs. If a provably correct class is specialised we like to know those correctness properties which are preserved in the subclass. This can avoid re-verification of already proven properties and may thus substantially reduce the verifi-cation effort. In this paper we study the question of inheritance of correctness prop-erties in the context of state-based formalisms, using a temporal logic (CTL) to formalise requirements on classes. Given a superclass and its specialised subclass we develop a technique for computing the set of for-mulas which are preserved in the subclass. For specialisation we allow addition of attributes, modification of existing as well as extension with new methods.

Analytical Pluralism in Qualitative Research: A Meta-Study

Recent interest in analytical pluralism – the application of more than one qualitative analytical method to a single data set – has demonstrated its potential to produce multiple, complex and varied understandings of phenomena. However tensions remain regarding the commensurability of findings produced from diverse theoretical frameworks, the practical application of multiple methods of analysis and the capacity of pluralism to contribute to knowledge in psychology. This study addresses these issues, through a critical interpretation of existing qualitative studies that utilised analytical pluralism. Using a meta-study design, we examined the use of theory, application of methods and production of findings in studies that had adopted qualitative analytical pluralism. Following comprehensive database searches, 10 articles were included in the analysis. Epistemological and ontological considerations, the influence of decisions made in the practical application of pluralism and approaches to interpreting findings produced from multiple analyses are discussed, and implications for future research are considered

Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain

AbstractAngiotensin-converting enzyme-2 (ACE2) is a regulatory protein of the renin–angiotensin system (RAS) and a receptor for the causative agent of severe-acute respiratory syndrome (SARS), the SARS-coronavirus. We have previously shown that ACE2 can be shed from the cell surface in response to phorbol esters by a process involving TNF-α converting enzyme (TACE; ADAM17). In this study, we demonstrate that inhibitors of calmodulin also stimulate shedding of the ACE2 ectodomain, a process at least partially mediated by a metalloproteinase. We also show that calmodulin associates with ACE2 and that this interaction is decreased by calmodulin inhibitors

Feasibility of trial procedures for a randomised controlled trial of a community based group exercise intervention for falls prevention for visually impaired older people: the VIOLET study

Background Visually impaired older people (VIOP) have a higher risk of falling than their sighted peers, and are likely to avoid physical activity. The aim was to adapt the existing Falls Management Exercise (FaME) programme for VIOP, delivered in the community, and to investigate the feasibility of conducting a definitive randomised controlled trial (RCT) of this adapted intervention. Methods Two-centre randomised mixed methods pilot trial and economic evaluation of the adapted group-based FaME programme for VIOP versus usual care. A one hour exercise programme ran weekly over 12 weeks at the study sites (Newcastle and Glasgow), delivered by third sector (voluntary and community) organisations. Participants were advised to exercise at home for an additional two hours over the week. Those randomised to the usual activities group received no intervention. Outcome measures were completed at baseline, 12 and 24 weeks. The potential primary outcome was the Short Form Falls Efficacy Scale – International (SFES-I). Participants’ adherence was assessed by reviewing attendance records and self-reported compliance to the home exercises. Adherence with the course content (fidelity) by instructors was assessed by a researcher. Adverse events were collected in a weekly phone call. Results Eighteen participants, drawn from community-living VIOP were screened; 68 met the inclusion criteria; 64 participants were randomised with 33 allocated to the intervention and 31 to the usual activities arm. 94% of participants provided data at the 12 week visit and 92% at 24 weeks. Adherence was high. The intervention was found to be safe with 76% attending nine or more classes. Median time for home exercise was 50 min per week. There was little or no evidence that fear of falling, balance and falls risk, physical activity, emotional, attitudinal or quality of life outcomes differed between trial arms at follow-up. Conclusions The intervention, FaME, was implemented successfully for VIOP and all progression criteria for a main trial were met. The lack of difference between groups on fear of falling was unsurprising given it was a pilot study but there may have been other contributory factors including suboptimal exercise dose and apparent low risk of falls in participants. These issues need addressing for a future trial